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Alzheimer's disease (AD) is a progressive, dementing, whole-body disorder that presents with decline in cognitive, behavioral, and emotional functions, as well as endocrine dysregulation. The etiology of AD is not fully understood but stress- and anxiety-related hormones may play a role in its development and trajectory. The glucocorticoid cascade hypothesis posits that levels of glucocorticoids increase with age, leading to dysregulated negative feedback, further elevated glucocorticoids, and resulting neuropathology. We examined the impact of age (from 2 to 10 months) and stressor exposure (predator odor) on hormone levels (corticosterone and ghrelin), anxiety-like behavior (open field and light dark tests), and memory-related behavior (novel object recognition; NOR), and whether these various measures correlated with neuropathology (hippocampus and cortex amyloid beta, Aβ) in male and female APPswe/PS1dE9 transgenic and non-transgenic mice. Additionally, we performed exploratory analyses to probe if the open field and light dark test as commonly used tasks to assess anxiety levels were correlated. Consistent with the glucocorticoid cascade hypothesis, baseline corticosterone increased with age. Predator odor exposure elevated corticosterone at each age, but in contrast to the glucocorticoid cascade hypothesis, the magnitude of stressor-induced elevations in corticosterone levels did not increase with age. Overall, transgenic mice had higher post-stressor, but not baseline, corticosterone than non-transgenic mice, and across both genotypes, females consistently had higher (baseline and post-stressor) corticosterone than males. Behavior in the open field test primarily showed decreased locomotion with age, and this was pronounced in transgenic females. Anxiety-like behaviors in the light dark test were exacerbated following predator odor, and female transgenic mice were the most impacted. Compared to transgenic males, transgenic females had higher Aβ concentrations and showed more anxiety-like behavior. Performance on the NOR did not differ significantly between genotypes. Lastly, we did not find robust, statistically significant correlations among corticosterone, ghrelin, recognition memory, anxiety-like behaviors, or Aβ, suggesting outcomes are not strongly related on the individual level. Our data suggest that despite Aβ accumulation in the hippocampus and cortex, male and female APPswePS1dE9 transgenic mice do not differ robustly from their non-transgenic littermates in physiological, endocrine, and behavioral measures at the range of ages studied here., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Sex differences are a well-known phenomenon in Alzheimer's disease (AD), with women having a higher risk for AD than men. Many AD mouse models display a similar sex-dependent pattern, with females showing earlier cognitive deficits and more severe neuropathology than males. However, whether those differences are relevant to human disease is unclear. Here we show that in AD mouse models that overexpress amyloid precursor protein (APP) under control of the prion protein promoter (PrP), female transgenic mice have higher APP expression than males, complicating interpretations of the role of sex-related factors in such models. By contrast, in a tTa:APPsi model, in which APP expression is driven by the tetracycline transactivator (tTa) from the CaMKIIα promoter, there are no sex-related differences in expression or processing of APP. In addition, the levels of Aβ dimers and tetramers, as well as Aβ peptide accumulation, are similar between sexes. Behavioral testing demonstrated that both male and female tTa:APPsi mice develop age-dependent deficits in spatial recognition memory and conditional freezing to context. These cognitive deficits were accompanied by habituation-associated hyperlocomotion and startle hyper-reactivity. Significant sex-related dimorphisms were observed, due to females showing earlier onsets of the deficits in conditioned freezing and hyperlocomotion. In addition, tTa:APPsi males but not females demonstrated a lack of novelty-induced activation. Both males and females showed atrophy of the dentate gyrus (DG) of the dorsal hippocampus, associated with widening of the pyramidal layer of the CA1 area in both sexes. Ventral DG was preserved. Sex-related differences were limited to the DG, with females showing more advanced degeneration than males. Collectively, our data show that the tTa:APPsi model is characterized by a lack of sex-related differences in APP expression, making this model useful in deciphering the mechanisms of sex differences in AD pathogenesis. Sex-related dimorphisms observed in this model under conditions of equal APP expression between sexes suggest a higher sensitivity of females to the effects of APP and/or Aβ production., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The HD-N171-82Q (line 81) mouse model of Huntington's disease (HD), expresses an N-terminal fragment of mutant huntingtin (htt), loses motor function, displays HD-related pathological features, and dies prematurely. In the present study, we compare the efficacy with which environmental, pharmacological, and genetic interventions ameliorate these abnormalities. As previously reported for the R6/2 mouse model of HD, housing mice in enriched environments improved the motor skills of N171-82Q mice. However, life expectancy was not prolonged. Significant improvements in motor function, without prolonging survival, were also observed in N171-82Q mice treated with Coenzyme Q10 (CoQ10, an energy metabolism enhancer). Several compounds were not effective in either improving motor skills or prolonging life, including Remacemide (a glutamate antagonist), Celecoxib (a COX-2 inhibitor), and Chlorpromazine (a prion inhibitor); Celecoxib dramatically shortened life expectancy. We also tested whether raising cellular antioxidant capacity by co-expressing high levels of wild-type human Cu/Zn superoxide dismutase 1 (SOD1) was beneficial. However, no improvement in motor performance or life expectancy was observed. Although we would argue that positive outcomes in mice carry far greater weight than negative outcomes, we suggest that caution may be warranted in testing Celecoxib in HD patients. The positive outcomes achieved by CoQ10 therapy and environmental stimuli point toward two potentially therapeutic approaches that should be readily accessible to HD patients and at-risk family members.

Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of beta-amyloid (Abeta), neuritic plaques, and glial responses. In studies of cognition in these animals, there have been several reports of memory disturbances well before the appearance of amyloid deposits. We have developed two distinct lines of transgenic mice (C3-3 and E1-2) that express the "Swedish" variant of APP (APP(SWE)) at levels that are approximately three-fold higher than endogenous mouse APP. Both lines have been backcrossed to C57BL/6J mice for 10 generations. Here, we use longitudinal and cross-sectional studies to evaluate the cognitive performance of our animals, where the concentration of Abeta1-42 in brain increases with aging from low levels (2-10 pmol/g) at 6-14 months of age to relatively high levels (60-100 pmol/g) at 24-26 months, when deposits of Abeta were beginning to form. When 12-month-old mice were tested in tasks that assess reference and working memory, transgenic mice from both lines could not be distinguished from nontransgenic littermates. Further study of 24- to 26-month-old transgenic mice (C3-3 line) found no evidence of memory impairment despite the presence of high levels of human Abeta (60-100 pmol/g). Thus, the expression of APP(SWE) at approximately three-fold over endogenous levels, which is sufficient to induce amyloid deposition at advanced ages, does not significantly erode cognitive performance in aged mice.

In the present study, the effect of previous experience on spatial memory, which required the retention of information either over long intervals or within a single session, was longitudinally tested in the water maze in male F-344 rats that were from 6 to 24 months of age. Performance in these tasks was found to be age-dependent (Markowska, 1999). Other behavioral tasks in the straight alley and with a visible platform in the water maze controlled the noncognitive components of performance. For all tasks, performance was significantly correlated between 12-month-old and 18-month-old rats, indicating that cognitive performance at the early, but not advanced, stage of aging could be predicted from performance at a younger age if the novelty of the first exposure to the task was eliminated. The protective effect of experience was more robust in the reference memory task as compared to the working memory task and was modified by age when training was initiated. Behavior during the probe trials was more sensitive to the effect of aging and more resistant to the beneficial effect of practice as compared to the performance in the platform trials. The speed of swimming of experienced rats progressively decreased with age only when tested in the cognitive tasks but not in the straight alley. This indicates that speed of swimming during cognitive tasks does not exclusively reflect the ability to swim, but might be also affected by the cognitive demands of the task. Protective effect of experience on cognition was not modified by restriction in diet.